In the United Sates, prostate cancer is the second leading cause of cancer-related deaths, and African- American men have long been known to exhibit a higher incidence and increased mortality compared to men of other ethnic groups. Although socioeconomic factors and unequal access to health care undoubtedly contribute to this disparity, differences in incidence and outcome persist after adjusting for these factors. Thus, tumor biological and/or genetic aspects may underpin adverse outcomes in African-American prostate cancer. To date, however, few studies have queried the molecular biology or somatic genetics of African-American prostate cancer in-depth, meaning that our understanding of the spectrum of factors influencing these disparities remains incomplete. The over-arching goal of this proposal is to undertake a definitive somatic genetic and functional characterization of African-American prostate cancer. To accomplish this goal, we will develop a targeted, massively parallel sequencing platform that interrogates the spectrum of recurrent alterations (base mutations, chromosomal copy number changes, and selected chromosomal rearrangements) relevant to prostate cancer. We will utilize this platform to perform tumor mutation profiling in a cohort of two hundred prostate tumor specimens obtained from African American men, leveraging knowledge from prostate cancer genome sequencing studies currently ongoing at the Broad Institute and elsewhere. Patterns of somatic alterations observed in this cohort will be compared to those of European-American prostate cancer. In addition, we will test top candidate genes affected by recurrently altered prostate cancer genomic loci for effects on the tumorigenic phenotype in primary prostate epithelial cells obtained from men of European or African descent. Once completed, this project should provide decisive insights into the spectrum of and functional relevance of somatic genetic alterations in African-American prostate cancer, thereby affirming or refuting the hypothesis that these biological factors undergird this pervasive cancer health disparity. PUBLIC HEALTH RELEVANCE: Prostate cancer in African-American men occurs more frequently, earlier in life, and with increased lethality when compared to European Americans. Undoubtedly, the genesis of this profound disparity is multi-factorial; however, a detailed study of the genetics and biology of African-American prostate cancer has not previously been undertaken. The focus of this grant is a systematic study of recurrent somatic genetic alterations in African-American prostate cancer using targeted, massively parallel sequencing. In addition, we will query specific cancer alterations in cell culture models derived from African-American and European-American patients. Upon completion, this study will likely constitute one of the most comprehensive functional genetic efforts yet undertaken in African-American prostate cancer. Insights from this study may inform new treatment strategies that prove broadly relevant across diverse human populations.